Chronic neurodegenerative diseases are a significant health problem for the elderly, causing profound morbidity and mortality, and generating staggering health care related expenses. Mechanisms that regulate the late onset and severity of phenotype of these disorders are poorly understood. To address this question we have chosen to study Kennedy's disease, a degenerative disorder of motor neurons caused by a CAG/glutamine expansion in the androgen receptor. The laboratory's long-range goal is to understand the mechanisms by which expansions of glutamine tracts cause neuronal dysfunction and death. The objective of this application is to identify pathways that modify toxicity of the mutant androgen receptor, and may therefore impact age of onset and severity of phenotype. Our central hypothesis is that toxicity is modified both by the unfolded protein response (UPR) and by decreased receptor acetylation. The rationale of these studies is that understanding pathways that modify toxicity of the mutant protein will yield insights into the mechanisms of neurodegeneration, thereby suggesting novel therapeutic targets. The central hypothesis will be tested by pursuing the following specific aims: 1) Establish that the UPR is a modifier of polyglutamine toxicity; 2) Determine the extent to which decreased acetylation of the expanded glutamine androgen receptor contributes to misfolding and aggregation; and 3) Determine the extent to which 113 CAG repeats targeted to the mouse androgen receptor gene causes selective dysfunction or degeneration of motor neurons, UPR activation and decreased receptor acetylation in vivo. It is my expectation that receipt of the Beeson Award will enable me to gain critical skills and experience in aging research. At the completion of these studies, we expect to establish that misfolding, aggregation and toxicity of the mutant androgen receptor is modified by the UPR and by pathways that mediate ligand-dependent androgen receptor acetylation. We also expect that our knock-in mouse model will reproduce important aspects of this disorder, including selective motor neuron dysfunction and degeneration. Such outcomes will have general impact by furthering our understanding of disease pathogenesis and by yielding a mouse model that faithfully recapitulates the human disease. [unreadable] [unreadable] [unreadable] [unreadable]